Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19-20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

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The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years, p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years, p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n = 12), ulcer disease (n = 6), hypercalcemia/uremia (n = 3), carcinoid tumor (n = 6), and nonendocrine malignancies (n = 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

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